Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conjugate vaccines consisting of the capsular polysaccharide (PS) of Haemophilus influenzae type b (Hib) covalently linked to carrier proteins, unlike pure PS, are immunogenic in infants and have significantly reduced Hib infections in the United States, but require multiple doses to induce protective anti-PS Ab titers. Hib-meningococcal outer membrane protein complex (OMPC) conjugate vaccine, however, elicits protective anti-PS Ab titers after one dose. We found that OMPC and Hib-OMPC engaged human Toll-like receptor 2 (TLR2) expressed in human embryonic kidney (HEK) cells, inducing IL-8 production, and engaged mouse TLR2 on bone marrow-derived dendritic cells, inducing TNF release. Hib conjugated to the carrier proteins CRM(197) and tetanus toxoid did not engage TLR2 on HEK or dendritic cells. Engagement of TLR2 by Hib-OMPC was MyD88 dependent, as Hib-OMPC-induced TNF production was ablated in MyD88 knockout (KO) mice. Hib-OMPC was significantly less immunogenic in TLR2 KO mice, inducing lower Hib PS IgG and IgM titers compared with those in wild-type mice. Splenocytes from OMPC-immunized TLR2 KO mice also produced significantly less IL-6 and TNF-alpha than those from wild-type mice. Hib-OMPC is unique among glycoconjugate vaccines by engaging TLR2, and the ability of Hib-OMPC to elicit protective levels of Abs after one dose may be related to TLR2-mediated induction and regulation of cytokines produced by T cells and macrophages in addition to the peptide/MHC II-dependent recruitment of T cell help commonly afforded by carrier proteins. TLR2 engagement by an adjuvant or carrier protein may be a useful strategy for augmentation of the anti-PS Ab response induced by glycoconjugate vaccines.
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PMID:Haemophilus influenzae type b-outer membrane protein complex glycoconjugate vaccine induces cytokine production by engaging human toll-like receptor 2 (TLR2) and requires the presence of TLR2 for optimal immunogenicity. 1476 14

Cattle are a major reservoir of Escherichia coli 0157:H7, an important zoonotic pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome (HUS). Colonization of cattle occurs predominantly in the large intestine, and may especially target follicle-associated epithelium (FAE) in the terminal rectum. Bacterial colonization involves induction of attaching-effacing (A/E) lesions, mediated by type III secreted proteins and an outer membrane protein called intimin. ToxB, encoded on plasmid pO157, contributes to adherence of E. coli O157:H7 through promotion of the production and/or secretion of type III secreted proteins. Production of type III secreted proteins and intestinal colonization appear to involve quorum-sensing mechanisms. In the human host, E. coli O157:H7 may have a preference for FAE in the distal small intestine. The H7 flagellum induces production of chemokines such as interleukin 8, and neutrophilic infiltration of the intestinal mucosa, which in turn may enhance Shiga toxin (Stx) uptake across the intestinal epithelium. Both Stx and cytokine responses play critical roles in the induction of the vascular lesions that underlie hemorrhagic colitis and HUS. In cattle, Stx binds to intestinal crypt cells and submucosal lymphocytes but not vascular endothelium. The role played by Stx in cattle may be to suppress mucosal immunity, yet enhance other effects that promote intestinal colonization.
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PMID:Escherichia coli 0157:H7: an update on intestinal colonization and virulence mechanisms. 1546 May 38

Neisseria meningitidis traversal across the blood-cerebrospinal fluid barrier is an essential step in the pathogenesis of bacterial meningitis. We have previously shown that invasion of human brain microvascular endothelial cells (HBMEC) by meningococci is mediated by bacterial outer membrane protein Opc that binds fibronectin, thereby anchoring the bacterium to the integrin alpha 5 beta 1-receptor on the endothelial cell surface. However, subsequent signal transduction mechanisms essential for or regulated by N. meningitidis adhesion and invasion, or HBMEC responses to N. meningitidis are unknown. In this report we investigated the role of c-Jun N-terminal kinases 1 and 2 (JNK1 and JNK2), p38 mitogen-activated (MAP) kinase and protein tyrosine kinases in endothelial-N. meningitidis interaction. Binding of meningococci to HBMEC phosphorylated and activated JNK1 and JNK2 and p38 MAPK as well as their direct substrates c-Jun and MAP kinase activated kinase-2 (MAPKAPK-2), respectively. Non-invasive meningococcal strains lacking opc gene (opc mutants and sequence type 11 complex meningococci) still activated p38 MAPK, however, failed to activate JNK. Inhibition of JNK1 and JNK2 significantly reduced internalization of N. meningitidis by HBMEC without affecting its adherence. Blocking the endothelial integrin alpha 5 beta 1 also decreased N. meningitidis-induced JNK activation in HBMEC. These findings indicate the crucial role of JNK signalling pathway in N. meningitidis invasion in HBMEC. In contrast, p38 MAPK pathway was important for the control of interleukin-6 (IL-6) and IL-8 release by HBMEC. Genistein, a protein tyrosine kinase inhibitor, decreased both invasion of N. meningitidis into HBMEC and IL-6 and IL-8 release, indicating that protein tyrosine kinases, which link signals from integrins to intracellular signalling pathways are essential for both bacterial internalization and cytokine secretion by HBMEC.
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PMID:Interaction of Neisseria meningitidis with human brain microvascular endothelial cells: role of MAP- and tyrosine kinases in invasion and inflammatory cytokine release. 1552 95

Interactions of nontypeable Haemophilus influenzae (NTHI) with human macrophages contribute to the pathogenesis of NTHI-induced infection in humans. However, the immunologic mechanisms that initiate and perpetuate NTHI-mediated macrophage responses have not been well explored. Outer membrane protein (OMP) P6 is a conserved lipoprotein expressed by NTHI in vivo that possesses a Pam(3)Cys terminal motif, characteristic of immunoactive bacterial lipoproteins associated with Toll-like receptor signaling. We theorized that OMP P6 is a potent immunomodulator of human macrophages. To test this hypothesis, we purified OMP P6 as well as OMP P2, the predominant NTHI outer membrane protein, and lipooligosaccharide (LOS), the specific endotoxin of NTHI, from NTHI strain 1479. Human blood monocyte-derived macrophages, purified from healthy donors, were incubated with each outer membrane constituent, and cytokine production of macrophage supernatants interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), IL-10, IL-12, and IL-8 was measured. OMP P6 selectively upregulated IL-10, TNF-alpha, and IL-8. While OMP P6 (0.1 mug/ml for 8 h) elicited slightly greater concentrations of IL-10, it resulted in over ninefold greater concentrations of TNF-alpha and over fourfold greater concentrations of IL-8 than did OMP P2. OMP P6 at doses as low as 10 pg/ml was still effective at induction of macrophage IL-8, while OMP P2 and LOS were not. OMP P6 of NTHI is a specific trigger of bacteria-induced human macrophage inflammatory events, with IL-8 and TNF-alpha as key effectors of P6-induced macrophage responses.
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PMID:Outer membrane protein P6 of nontypeable Haemophilus influenzae is a potent and selective inducer of human macrophage proinflammatory cytokines. 1584 75

Phagocytes are well-known effectors of the innate immune system to produce proinflammatory cytokines and chemokines such as tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-8 during infections. Here, we show that infection of monocytes with wild-type Escherichia coli K1, which causes meningitis in neonates, suppresses the production of cytokines and chemokines (TNF-alpha, regulated on activation, normal T expressed and secreted, macrophage-inflammatory protein-1beta, IL-1beta, and IL-8). In contrast, infection of monocytes with a mutant E. coli, which lacks outer membrane protein A (OmpA- E. coli) resulted in robust production of cytokines and chemokines. Wild-type E. coli K1 (OmpA+ E. coli) prevented the phosphorylation and its degradation of inhibitor of kappaB, thereby blocking the translocation of nuclear factor (NF)-kappaB to the nucleus. OmpA+ E. coli-infected cells, subsequently subjected to lipopolysaccharide challenge, were crippled severely in their ability to activate NF-kappaB to induce cytokine/chemokine production. Selective inhibitors of the extracellular signal-regulated kinase (ERK) 1/2 pathway and p38 mitogen-activated protein kinase (MAPK), but not Jun N-terminal kinase, significantly reduced the activation of NF-kappaB and the production of cytokines and chemokines induced by OmpA- E. coli, indicating a role for these kinases in the NF-kappaB/cytokine pathway. It is interesting that the phosphorylation of ERK 1/2 and p38 MAPK was notably reduced in monocytes infected with OmpA+ E. coli when compared with monocytes infected with OmpA- E. coli, suggesting that the modulation of upstream events common for NF-kappaB and MAPKs by the bacterium is possible. The ability of OmpA+ E. coli K1 to inhibit the macrophage response temporarily may enable bacterial survival and growth within the host for the onset of meningitis by E. coli K1.
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PMID:Escherichia coli K1 inhibits proinflammatory cytokine induction in monocytes by preventing NF-kappaB activation. 1589 82

Helicobacter pylori (H pylori), one of the most common bacterial pathogens on human beings, colonizes the gastric mucosa. In its 95 paralogous gene families, there is a large outer membrane protein (OMP) family. It includes 32 members. These OMP are important for the diagnosis, protective immunity, pathogenicity of H pylori and so on. They are significantly associated with high H pylori density, the damage of gastric mucosa, high mucosal IL-8 levels and severe neutrophil infiltration. We introduce their research progress on pathogenicity.
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PMID:Research progress on Helicobacter pylori outer membrane protein. 1591 81

A major mechanism for apical peptide absorption by small intestine is via the proton-coupled transporter PepT1. PepT1 is expressed at a high level in proximal small intestine, but it is not expressed in the healthy colon. However, in chronic states of intestinal inflammation, such as in Crohn's disease and ulcerative colitis, PepT1 expression in colonic epithelia is increased, serving as a pathway for entry of bacteria-derived molecules such as muramyl dipeptide (MDP) and fMet-Leu-Phe (fMLP). As little is known of how inflammation induces PepT1, we investigated whether or not inflammatory cytokines and mediators such as interleukins (IL)-1beta, IL-2, IL-8, IL-10, tumor necrosis factor-alpha, (TNF-alpha) and interferon-gamma (IFN-gamma ) up-regulate PepT1 activity and expression. Uptake of the PepT1 substrate glycylsarcosine [(3)H]-Gly-Sar was studied in vitro in the human colon carcinoma cell line Caco2/bbe monolayers as well as in vivo in mice injected with cytokines. TNF-alpha and IFN-gamma increased the activity, and total and apical membrane protein expression of PepT1 protein in a concentration- and time-dependent fashion. No changes in PepT1 mRNA were observed, suggesting post-transcriptional regulation. All three cytokines increased PepT1 protein expression in mouse proximal and distal colon but not in jejunum or ileum. TNF-alpha and IFN-gamma, but not IL-1beta, increased Gly-Sar uptake in mouse proximal and distal colon; however, no changes were observed in the small intestine with any cytokine treatment. Whereas neither TNF-alpha nor IFN-gamma increased PepT1 mRNA expression in any segment of the intestine, treatment with IL-1beta increased PepT1 mRNA expression in mouse proximal and distal colon and decreased PepT1 mRNA expression in jejunum and ileum. Since PepT1 transports bacteria-derived peptides, the up-regulation of protein expression and activity observed after treatment with TNF-alpha or IFN-gamma may play a role in activating host responses in involved colon.
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PMID:Tumor necrosis factor-alpha and interferon-gamma increase PepT1 expression and activity in the human colon carcinoma cell line Caco-2/bbe and in mouse intestine. 1632 52

CD43 is a heavily O-glycosylated type I trans-membrane protein, expressed at high levels on the surface of leukocytes. It is frequently overexpressed in early colon adenomas, but not in normal colon epithelial cells. To identify CD43 target genes, gene array analysis was performed using a tetracycline-inducible CD43 expression system in human colon adenocarcinoma SW480 cells. CD43 was demonstrated to down-regulate a variety of chemokine genes. Overexpression of CD43 suppressed constitutive as well as PMA-induced NF-kappaB activation and reduced the DNA binding of transcription factor p65 but not p50. Furthermore, a reduced NF-kappaB responsive promoter activity was observed and a decreased expression of proinflammatory chemokines MCP-1, IL-8 and GRO-alpha. These results suggest that overexpression of CD43 suppresses a subset of NF-kappaB target genes, partly via the inhibition of p65 transcriptional activity.
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PMID:Inhibition of NF-kappaB activation and chemokine expression by the leukocyte glycoprotein, CD43, in colon cancer cells. 1646 75

Our previous report has shown that Irsogladine maleate (IM) counters and obviates the reduction in gap junction intercellular communication (GJIC) and the increase in IL-8 levels, respectively, induced by outer membrane protein 29 from Actinobacillus actinomycetemcomitans (A. actinomycetemcomitans) in cultured human gingival epithelial cells (HGEC). In addition, IM suppresses the increase in the secretion of IL-8 caused by whole live A. actinomycetemcomitans. These findings implicate the modulation of IL-8 levels by IM in abolishment of the reduction of GJIC in HGEC. Tight junctions are also responsible for cell-cell communication. Zonula occludens protein-1 (ZO-1) is a major tight junction protein. To investigate the regulatory mechanism of intercellular communication mediated by IM, in the present study, we focused on the involvement of IL-8 in A. actinomycetemcomitans-induced change in GJIC and ZO-1 expression in HGEC. IM countered the A. actinomycetemcomitans-induced reduction in levels of Connexin (CX) 43, suggesting that it could abolish the A. actinomycetemcomitans-induced reduction in GJIC in HGEC. CXCR-1 is a receptor of IL-8. The simultaneous addition of A. actinomycetemcomitans and anti-CXCR-1 antibody also abrogated the repression of GJIC and CX43 expression by A. actinomycetemcomitans in HGEC, although the anti-CXCR-1 antibody was less effective than IM. IM inhibited the IL-8-induced reduction in CX43 levels and GJIC in HGEC. IM countered the A. actinomycetemcomitans-induced reduction in the expression of ZO-1, although anti-CXCR-1 antibody did not influence the decrease in ZO-1 mRNA levels caused by A. actinomycetemcomitans. Furthermore, IL-8 had little effect on the mRNA levels of ZO-1. These findings suggest that IL-8 mediates the A. actinomycetemcomitans-induced reduction of GJIC and CX43 expression in HGEC. The regulation of IL-8 levels by IM in HGEC is partially involved in abrogation of the reduction of GJIC and CX43 expression by A. actinomycetemcomitans. Furthermore, the regulatory effect of IM on the expression of CX43 and ZO-1 is different.
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PMID:Regulation of IL-8 by Irsogladine maleate is involved in abolishment of Actinobacillus actinomycetemcomitans-induced reduction of gap-junctional intercellular communication. 1687 Apr 66

Antimicrobial peptides, human beta-defensin (hBD), and the 18-kDa cationic antimicrobial protein (CAP18) are components of innate immunity. These peptides have antimicrobial activity against bacteria, fungi, and viruses. Actinobacillus actinomycetemcomitans is a gram-negative facultative anaerobe implicated in the initiation of periodontitis. The innate immunity peptides have antibacterial activity against A. actinomycetemcomitans. We investigated the molecular mechanism of human gingival epithelial cells (HGEC) responding to exposure to A. actinomycetemcomitans. HGEC constitutively express hBD1 and inducibly express hBD2, hBD3, and CAP18 on exposure to A. actinomycetemcomitans. The level of expression varies among clinical isolates. In the signaling pathway for hBD2 induction by the bacterial contact, we demonstrate that the mitogen-activated protein (MAP) kinase and not the NF-kappaB transcription factor pathway is used. We found the outer membrane protein 100 (Omp100; identified by molecular mass) is the component inducing the hBD2 response. Omp100 binds to fibronectin, an extracellular matrix inducing hBD2 via the MAP kinase pathway. Anti-integrin alpha(5)beta(1), antifibronectin, genistein, and PP2 suppress the Omp100-induced expression of hBD2, suggesting that Src kinase is involved through integrin alpha(5)beta(1). The inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6 and IL-8, produced by HGEC on contact with A. actinomycetemcomitans also stimulate expression of hBD2. Further, neutralizing antibody against TNF-alpha or IL-8 partially inhibits the induction of hBD2 on bacterial contact. Therefore, we found that the induction of the antimicrobial peptides is mediated by a direct response principally through an Omp100-fibronectin interaction, and using secondary stimulation by inflammatory cytokines induced by the bacterial exposure.
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PMID:Actinobacillus actinomycetemcomitans outer membrane protein 100 triggers innate immunity and production of beta-defensin and the 18-kilodalton cationic antimicrobial protein through the fibronectin-integrin pathway in human gingival epithelial cells. 1692 14


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